Oxadiazole derivatives



OXADIAZOLE DERIVATIVES Jack Bernstein and Harry Louis Yale, NewBrunswick,

L, assiguors to 01in Mathieson Chemical Corporatron, New York, N. Y., acorporation of Virginia No Drawing. Application February 6, 1957 SerialNo. 638,442

10 Claims. (Cl. 260-307) This invention relates to new compounds and,more particularly, to compounds selected from the class consisting ofoxadiazoles of the general formula lr and acid-addition salts thereof,wherein R is hydrogen or acyl and R is aralkyl (preferably a hydrocarbonaralkyl of less than 15 carbon atoms, as exemplified by benzyl,phenethyl, a-phenylpropyl, benzhydryl and methylbenzyl).

The compounds of this invention are' effective as skeletalmuscle-relaxants, tranquilizing agents and especially antiepilepticagents. Thus, they may be used in the prevention of epileptic seizures,both of the grand mal and petit mal type. For this purpose, they areadministered perorally in a daily dosage of less than about 5 grams.

Exemplary compounds within the scope of this invention include:S-(hydrocarbon aryl-lower aIkyD-Z-amino- 1,3,4-oxadiazoles [e. g.,5-(a-ethylbenzyl)-2-amino-l,3,4- oxadiazole and particularlyS-diphenylmethyl-Z-amino- 1,3,4-oxadiazole] the acid-addition salts ofthe foregoing (particularly the acid-addition salts with strong mineralacids, such as hydrochloric, sulfuric and nitric acid); and the Z-N-acylderivatives thereof [particularly carboxylic acid amides, such as thealkanoic acid amides, as exemplified byS-benzhydryl-Z-acetamido-1,3,4-oxadiazole, S-(a-ethylbenzyl) 2laurylamido 1,3,4 oxadiazole and5-benzhydryl-Z-isovaleramido-1,3,4-oxadiazole].

These compounds are prepared by heating al-substituted-3-thiosemicarbazide of the formula with lead oxide andrecovering the resultant 5-R-substituted-Z-amino-1,3,4-oxadiazole. Thefree base, thus formed, can then, if desired, be converted to a Z-amidoderivative by heating with an acylating agent, preferably either an acylhalide or acid anhydride (e. g., an alkanoic acid anhydride such asacetic anhydride or an alkanoyl chloride such as lauryl chloride), or toits acid-addition salts by treatment with the desired acid.

The following examples illustrate the invention:

EXAMPLE 1 2-amin0-5-(u-ethylbenzyl) -1,3,4-xadiaz0le (a)J-(a-phenylbutyryl) 3 thi0semicarbazide.-To 27.3 g. of finely powderedthiosemicarbazide in 300 ml. of dry pyridine at 0 C. is added dropwise54.8 g. of a-phenylbutyryl chloride. The mixture is kept overnight,diluted with 700 ml. of Water, and concentrated in vacuo. The productseparates as an oil which soon solidifies. The yield ofl-(a-phenylbutyryl)-3thiosemicarbazide is about 25.3 g., M. P.approximately l66168 C.

(b) 2-amino (a ethylbenzyl)-1,3,4-0xadiaz0le.- A mixture of 5.8 g. ofl-(rx-phenylbutyryl)-3-thiosemicarbazide, 41.7 g. of Pb304 and 250 ml.of 95% ethanol 2,832,787 Patented Apr. 29, 1958 ice is stirred andrefluxed for 24 hours, filtered hot and the filtrate concentrated togive about 4 g. of 2-311'11110-5-(ocethylbenzyl)-1,3,4-oxadiazole, M. P.about ll96 C.

EXAMPLE 2 2 -amin0-5 -benzhydryZ-1 ,3,4 -0xadiaz0le 3y substituting 7.4g. of diphenylacetyl chloride for the a-phenylbutyryl chloride in theprocess of Example 1(a), about 3 g. of2-amino-5-benzhydryl-1,3,4-oxadiazole, M. P. about 2l1-212 C., isobtained.

EXAMPLE 3 Z-amino-S-(u-ethylbenzyl)-1,3,4-0xadiaz0le hydrochloride To 4g. of 2-amino-5-(oz-ethylbenzyl)-l,3,4-oxadiazole in an acetone solutionis added an equivalent amount of ethanolic hydrogen chloride. Thesolution thus formed is diluted with dry ether to give2-amino-5-(ot-ethyl benzyl)-1,3,4-oxadiazole hydrochloride, M. P. about134-135 C.

EXAMPLE 4 Z-acetamido-S-benzhydryl-1 ,3,4-0xadiaz0le 10 g. of2-amino-5-benzhydryl-1,3,4-oxadiazole and 25 ml. of acetic anhydride isrefluxed for one hour and the mixture allowed to cool. The solid whichcrystallizes is filtered to give about 9.5 g. ofZ-acetamido-S-benzhydryl- 1,3,4-oxadiazole.

EXAMPLE 5 Z-acemmido-S-(a-ethylbenzyl)-1,3,4-0xadiaz0le By substituting10 g. of 2-amino-5-(a-ethylbenzyD- 1,3,4-oxadiazole for the2-amino-5-benzhydryl-1,3,4-oxadiazole in the procedure of Example 4,Z-acetamido-S- (u-ethylbenzyl)-l,3,4-oxadiazole is obtained.

In a similar manner, other 2-acylated derivatives can be produced. Thus,by substituting propionic anhydride or lauryl chloride for the aceticanhydride in the procedure of either Example 4 or 5, the respective 2-propionyl and 2-lauryl derivatives are obtained.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

We claim:

1. A compound selected from the class consisting of oxadiazoles of thegeneral formula and acid-addition salts thereof, wherein R is selectedfrom the group consisting of hydrogen and a fatty carboxylic acylradical, and R is selected from the group consisting v of phenyl andlower alkyl.

2. 5-[a-(lower alkyl)benzyl] 2 amin0-1,3,4-oxadiazole.

3. An acid-addition salt of 5-[u-(lower alkyl)benzyll-Z-amino-1,3,4-oxadiazole.

4. 2-alkanoy1amino-S-benzhydryl-1,3,4-oxadiazole.

5. 2-alkanoylamino 5 [ct-(lower alkyl)benzyl]-1,3,4- oxadiazole.

6. 2-amino-5-benzhydryl-1,3,4-oxadiazole.

7. 2-amino-5-(ot-ethylbenzyl)-l,3,4-oxadiazole.

8. Z-amiHO-S-(oaethylbenzyl)-1,3,4-oxadiazole hydrochloride.

9. Z-acetamido-S-benzhydryl-1,3,4-oxadiazole.

l0. Z-acetamido-S-(a-ethylbenzyl)-1,3,4-oxadiazole.

References Cited in the file of this patent Valenti et al.: Chem.Abstracts, vol. 46, col. 11186 (1952). 1

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF OXADIAZOLES OF THEGENERAL FORMULA